反应详情

温度

80 °C

Dissolve [5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 3.20 g, 7.94 mmol and 2.0 equiv) and 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 1.37 g, 3.97 mmol, 1.0 equiv) in 7 mL of anhydrous DMSO, add diisopropylethyl amine (DIPEA, 1.36 mL, 7.94 mmol, 2.0 equiv) and heat in a sealed tube with stirring for 20 hours at 80° C. Pour the solution in a 1:1 v/v mixture of dichloromethane and iced water. Extract the aqueous phase with dichloromethane (2×50 mL), and wash the combined organic layers with water (2×50 mL) and aqueous sodium chloride (100 mL). Dry the organic solution over sodium sulfate and evaporate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient from 15% to 80% EtOAc in hexanes to afford 1.40 g of 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a pure foamy cream solid. 59% yield. ES+ (m/z) 597.4 [M+H].

1. temperatureheat in a sealed tube
2. additionPour the solution
3. extractionExtract the aqueous phase with dichloromethane (2×50 mL)
4. washwash the combined organic layers with water (2×50 mL) and aqueous sodium chloride (100 mL)
5. dry with materialDry the organic solution over sodium sulfate
6. customevaporate under reduced pressure
7. washSubject residue to silica gel chromatography eluting with a gradient from 15% to 80% EtOAc in hexanes